Abstract
There has been considerable debate as to whether obesity can act as an accelerator of type 1 diabetes (T1D). We assessed this possibility using transgenic mice (MIP-TF mice) whose ß-cells express enhanced green fluorescent protein (EGFP). Infecting these mice with EGFP-expressing murine herpes virus-68 (MHV68-EGFP) caused occasional transient elevation in their blood glucose, peri-insulitis, and Th1 responses to EGFP which did not spread to other ß-cell antigens. We hypothesized that obesity-related systemic inflammation and ß-cell stress could exacerbate the MHV68-EGFP-induced ß-cell autoreactivity. We crossed MIP-TF mice with Avy mice which develop obesity and provide models of metabolic disease alongside early stage T2D. Unlike their MIP-TF littermates, MHV68-EGFP–infected Avy/MIP-TF mice developed moderate intra-insulitis and transient hyperglycemia. MHV68-EGFP infection induced a more pronounced intra-insulitis in older, more obese, Avy/MIP-TF mice. Moreover, in MHV68-EGFP-infected Avy/MIP-TF mice, Th1 reactivity spread from EGFP to other ß-cell antigens. Thus, the spreading of autoreactivity among ß-cell antigens corresponded with the transition from peri-insulitis to intra-insulitis and occurred in obese Avy/MIP-TF mice but not lean MIP-TF mice. These observations are consistent with the notion that obesity-associated systemic inflammation and ß-cell stress lowers the threshold necessary for T cell autoreactivity to spread from EGFP to other ß-cell autoantigens.
Highlights
Epidemiologic studies have demonstrated that the incidence of type 1 diabetes (T1D) has been increasing globally over the past few decades, but the underlying reasons for this increase are not well understood[1,2]
We were initially interested whether infection with a recombinant adenovirus, lymphocytic choriomeningitis virus (LCMV) or murine gammaherpesvirus-68 virus (MHV68) that directed the expression of enhanced green fluorescent protein (GFP) (EGFP) could break self-tolerance to GFP in “mouse insulin promoter (MIP)-GFP” mice that express GFP in their ß-cells[23], and if so, would this neo-autoreactivity spread to other ß-cell antigens, promoting insulitis and T1D?
An elevation in the blood glucose levels of some MHV68-EGFP infected mice beginning about day 10 post-infection, this did not reach the level of overt hyperglycemia (>250 mg/dL, Fig. 1)
Summary
Epidemiologic studies have demonstrated that the incidence of type 1 diabetes (T1D) has been increasing globally over the past few decades, but the underlying reasons for this increase are not well understood[1,2]. We studied C57BL/6 “MIP-TF” mice that possess a transgene consisting of a mouse insulin promoter (MIP) linked to a trifusion (TF) protein of three linked imaging reporters; luciferase (for noninvasive charge-coupled device (CCD) imaging), a modified herpes virus thymidine kinase (for noninvasive microPET imaging) and EGFP (for fluorescent microscopy) of pancreatic islet ß-cells[24]. These mice express the trifusion reporter in their ß-cells and offer the opportunity to make non-invasive longitudinal assessments of ß-cells using CCD, as in our past studies of these mice with STZ-induced T1D or high fat diet-induced T2D24
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